Medicament for prevention or treatment of rhinovirus infection

ABSTRACT

The present invention provides a pharmaceutical composition for use in prevention or treatment of a human rhinovirus (HRV) infection. The composition comprises an aldohexose, wherein the hydroxyl group at carbon 2 of the aldohexose is replaced by any one of H, F, Cl, Br, I, SH, Me, OMe and SMe, such as a 2-deoxy-glucose. Furthermore, a dispenser for intranasal administration, such as a nasal spray or nose drop applicator containing said pharmaceutical composition is provided. In addition, an inhalation device, such as a metered-dose inhaler, a dry-powder inhaler or a nebuliser, comprising said composition is provided.

The present invention relates to pharmaceutical compositions for use inprevention or treatment of a human rhinovirus (HRV) infection, such asthe common cold.

HRV is an ssRNA non-enveloped virus of the family of the Picornaviridae.It causes the common cold, a condition responsible for several billiondollars of healthcare costs (Bertino, 2002), and is the causative agentof lower respiratory tract infection in the immunosuppressed (Kaiser etal., 2006; Liu et al., 2010) and both chronic obstructive pulmonarydisease (COPD) and asthma exacerbations (Papi et al., 2006; Steinke andBorish, 2016).

To date, therapeutic treatment options effective against HRV are verylimited. For instance, the antiviral pleconaril may have a marginaltreatment effect against HRV, which is however outweighed by the risk ofits side effects. Accordingly, the United States Food and DrugAdministration (FDA) rejected approval of pleconaril for treatment ofthe common cold (Fleischer and Laessig, 2003).

It is thus an object of the present invention to provide a prevention ortreatment which is relatively safe and effective against an HRVinfection, such as the common cold or a lower respiratory tractinfection, especially in an immunosuppressed individual or in anindividual having COPD or asthma.

SUMMARY OF THE INVENTION

Therefore, the present invention provides a pharmaceutical compositionfor use in prevention or treatment of an HRV infection. The compositioncomprises an aldohexose (in particular a D-aldohexose) such as glucose(preferably D-glucose) wherein the hydroxyl group at carbon 2 of thealdohexose is replaced by any one of the following substituents: H, F,Cl, Br, I, SH, methyl (Me), methoxy (OMe) and methylmercapto (SMe).Herein, an aldohexose compound according to this definition is alsocalled “the modified aldohexose”. In an especially preferred embodiment,the modified aldohexose is 2-deoxy-glucose.

In a further aspect, the present invention relates to a dispenser forintranasal administration such as a nasal spray, containing apharmaceutical composition comprising an aldohexose wherein the hydroxylgroup at carbon 2 of the aldohexose is replaced by any one of H, F, Cl,Br, I, SH, Me, OMe and SMe, in particular 2-deoxy-D-glucose.

In another aspect, the present invention relates to an inhalationdevice, such as a metered-dose inhaler, a dry-powder inhaler or anebuliser, for administration of a pharmaceutical composition preferablyto the lower respiratory tract, comprising a pharmaceutical compositioncomprising an aldohexose, wherein the hydroxyl group at carbon 2 of thealdohexose is replaced by any one of H, F, Cl, Br, I, SH, Me, OMe andSMe, preferably 2-deoxy-D-glucose.

In yet another aspect of the present invention, a method for delayingthe onset of or treating an HRV infection, comprising

-   -   obtaining a pharmaceutically acceptable formulation comprising        an aldohexose, wherein the hydroxyl group at carbon 2 is        replaced by any one of H, F, Cl, Br, I, SH, Me, OMe and SMe; and    -   administering an effective amount of the formulation to an        individual having the HRV infection or at risk of developing the        HRV infection, is provided.

In the course of the present invention, it was surprisingly found thattreatment with the modified aldohexose effectively inhibits HRVreproduction in-vitro (cf. example 1 and FIGS. 1 and 2) as well as invivo (cf. example 2 and FIGS. 3 and 4), without any measurable impact oncell viability. In vivo, no side effects were observed in connectionwith the inventive treatment. As the modified aldohexose targets HRVreplication itself, it is effective when administered after an HRVinfection has occurred (e.g. when the individual has already fallen illwith the common cold) as well as when administered before an HRVinfection has occurred (i.e. as a prophylactic measure, e.g. to delay orcompletely avoid onset of the disease or ameliorate or completelysuppress the symptoms of the disease). For instance, prophylacticadministration may be appropriate if a family member already showssymptoms of rhinitis.

While 2-deoxy-glucose was disclosed in the prior art to be effectiveagainst some enveloped viruses such as influenza virus (see e.g.Kilbourne, 1959 and Courtney et al., 1973), the prior art did notsuggest at all that 2-deoxy-glucose is effective against HRV infection.Specifically, influenza virus and HRV are both very distinct in theirstructure and pathophysiology. Influenza virus belongs to the unrelatedfamily of orthomyxoviridae, is enveloped and binds to sialic acidexpressing receptors for infection of epithelial cells (see Sun andWhittaker, 2013). In contrast, HRV is non-enveloped and most subtypesbind to ICAM-1 for host cell entry (Blaas and Fuchs, 2016). Apart fromthese differences, the viruses evolved very different strategies inendosomal escape and translation initiation (see Blaas and Fuchs, 2016,and Watanabe and Kawaoka, 2015). Consequently, the state-of-the arttherapy against influenza virus infections, oseltamivir, is noteffective against HRV. Moreover, an inhibitory capacity of2-deoxy-glucose on any human-pathogenic non-enveloped RNA viruses (suchas HRV) was not known in the prior art (cf. e.g. Kang and Hwang, 2006),making the effectiveness of the inventive HRV treatment all the moresurprising.

Completely unrelated to therapy, let alone prevention or treatment of aHRV infection, Ojima et al. (Annals of nuclear medicine 3 (1989):143-147) describe the preparation of a fine powder of2-deoxy-2-(¹⁸F)fluoro-D-glucose (¹⁸FDG) suitable for inhalation todiagnose non-infectious lung diseases by means of positron emissiontomography (PET). Also Venegas et al. (Database CA, Chemical AbstractsService, Database accession no. 2013:196451) describe the use of ¹⁸FDGfor PET imaging of the lung, again merely for diagnostic purposes andentirely unrelated to viral infection, let alone HRV infection.

Also unrelated to RNA viruses, DE 197 06 489 A1 discloses the use of2-deoxy-glucose for the suppression of viral DNA transcription invirus-associated lesions and/or neoplasms, which are caused by DNAviruses (e.g. human papillomavirus, hepatitis B virus, Epstein-Barrvirus).

Kang and Hwang describe the role of 2-deoxy-glucose as an anticancer andantiviral therapeutic. It is disclosed that 2-deoxy-glucose can inhibitmultiplication of some enveloped viruses (influenza virus, sindbis virusand semliki forest virus, herpes simplex virus, respiratory syncytialvirus and measles virus) by inhibiting viral envelope biosynthesis andvirion assembly. No inhibitory capacity on any non-enveloped RNA virusesis disclosed.

The effects of 2-deoxy-glucose on enveloped viruses have been describedin the prior art. For example, Schnitzer et al. (Virology 67 (1975)306-309) describe the effect of 2-deoxy-glucose and glucosamine on thegrowth and functions of respiratory syncytial and parainfluenza 3viruses. Kilbourne (Nature 183 (1959) 271-272) discloses the inhibitionof influenza virus multiplication by 2-deoxy-glucose. Hodes et al.(Virology 63 (1975) 201-208) describe the inhibition of respiratorysyncytial, parainfluenza 3 and measles viruses by 2-deoxy-glucose.However, prior to the present invention there was no indication that2-deoxy-glucose could also be effective against non-enveloped RNAviruses.

Unrelated to 2-deoxy-glucose, Arita et al. (Carbohydrate Research 62(1978) 143-154) disclose the synthesis of a variety of analogues andderivatives of phenyl glycosides and the examination of their antiviralactivity against some enveloped viruses (influenza virus and Herpessimplex virus).

In connection with all aspects of the present invention, the modifiedaldohexose contained in the pharmaceutical composition (orpharmaceutically acceptable formulation) preferably is one of compoundsI-VIII (depicted as Fischer projections):

wherein R is any one of H, F, Cl, Br, I, SH, Me, OMe and SMe. In otherwords, R replaces the hydroxyl group at carbon 2 of the respectivealdohexose. Compound I (i.e. the compound based on D-glucose) isparticularly preferred. 2-deoxy-D-glucose is compound I wherein R is H.2-deoxy-D-glucose is also called “2-DG” herein.

At present, three HRV species are known, namely Rhinovirus A, B and C.An overview over HRV taxonomy is for instance given in Palmenberg etal., 2009. Preferably, in connection with all aspects of the presentinvention, the HRV to be treated or prevented is a Rhinovirus A or B.

In the context of the present invention, the expression “pharmaceuticalcomposition” refers to any composition comprising at least one activeagent (e.g. the modified aldohexose), and preferably one or moreexcipients, which is pharmaceutically acceptable for administration (inparticular for topical administration or intranasal administration) toan individual, especially a mammal, in particular a human. Suitableexcipients are known to the person skilled in the art, for example water(especially water for injection), saline, Ringer's solution, dextrosesolution, buffers, Hank solution, vesicle forming compounds (e.g.lipids), fixed oils, ethyl oleate, 5% dextrose in saline, substancesthat enhance isotonicity and chemical stability, buffers andpreservatives, such as benzalkonium chloride. The pharmaceuticalcomposition according to the present invention may be liquid or ready tobe dissolved in liquid such as sterile, deionised or distilled water, orsterile isotonic phosphate-buffered saline (PBS). Preferably, 1000 μg(dry-weight) of such a composition comprises or consists of 0.1-990 μg,preferably 1-900 μg, more preferably 10-200 μg modified aldohexose, andoptionally 1-500 μg, preferably 1-100 μg, more preferably 5-15 μg(buffer) salts (preferably to yield an isotonic buffer in the finalvolume), and optionally 0.1-999.9 μg, preferably 100-999.9 μg, morepreferably 200-999 μg other excipients. Preferably, 100 mg of such a drycomposition is dissolved in sterile, de-ionised/distilled water orsterile isotonic phosphate-buffered saline (PBS) to yield a final volumeof 0.1-100 ml, preferably 0.5-20 ml, more preferably 1-10 ml. The dosageand method of administration, however, typically depends on theindividual to be treated. In general, the modified aldohexose may beadministered at a dose of between 1 μg/kg and 10 mg/kg, more preferablybetween 10 μg/kg and 5 mg/kg, most preferably between 0.1 and 2 mg/kg.

According to a particularly preferred embodiment of the presentinvention, the pharmaceutical composition is liquid and preferably anaqueous solution. In general, liquid compositions are especiallysuitable for intranasal administration, which is the preferred mode ofadministration.

In a further preferment, the concentration of the modified aldohexose,in particular 2-deoxy-D-glucose, is 0.01 mM-1000 mM, preferably 0.1mM-500 mM, more preferably 0.25 mM-250 mM, even more preferably 0.5mM-100 mM, in particular 1 mM-50 mM or even 2.5 mM-25 mM. Theseconcentration ranges are relatively safe and effective in connectionwith the inventive treatment.

The pharmaceutical composition may comprise further active agents, inparticular to further increase effectiveness or achieve further symptomreduction of the common cold. Thus, according to a further preferredembodiment, the pharmaceutical composition further comprises at leastone additional active agent. Preferably, the additional active agent isselected from the group consisting of decongestants, in particularnorepinephrine releasing agents (such as pseudoephedrine, ephedrine andphenylpropanolamine), α-adrenergic receptor agonists (such asoxymetazoline and xylometazoline), and corticosteroids (such asbudesonide, flunisolide, and fluticasone), and nonsteroidalanti-inflammatory drugs (NSAIDs) such as acetylsalicylic acid,ibuprofen, diclofenac, and phenylbutazone. Such agents can be expectedto act synergistically together with the modified aldohexose against arhinovirus infection such as rhinitis or the common cold. By contrast,the modified aldohexose such as 2-deoxy-D-glucose may also be the singleactive agent in the pharmaceutical composition (preferably in thepresence of one or more excipients).

The individual to be treated according to the present invention ispreferably a human individual, in particular an immunosuppressedindividual or an individual having COPD or asthma. According to apreferred embodiment, a dose of the pharmaceutical composition isadministered to a human individual, preferably intranasally (in otherwords: into a nostril of the individual, preferably into each nostrilindependently) and/or to a mucosal membrane, preferably a mucosalmembrane of the respiratory tract, in particular a mucosal membrane ofthe nasal cavity or of the lower respiratory tract. Advantageously, thedose is administered at least once every other day, preferably at leastonce per day, more preferably at least twice per day, in particular atleast thrice per day, and preferably for 2-14 days, more preferably for3-10 days, in particular for 4-7 days.

For relatively safe and effective treatment, according to a preference,the total amount of the modified aldohexose, in particular2-deoxy-D-glucose, in the dose is 0,001 μmol-100 μmol, preferably 0.01μmol-50 μmol, more preferably 0,025 μmol-25 μmol, even more preferably0.05 μmol-5 μmol, in particular 0.1 μmol-2.5 μmol or even 0.2 μmol-1.25μmol.

According to a particularly preferred embodiment, the pharmaceuticalcomposition (or pharmaceutically acceptable formulation) according tothe present invention is used for prevention or treatment of the commoncold, a rhinitis or a lower respiratory tract infection, especially inan immunosuppressed individual or in an individual having COPD orasthma. The term “preventing” or “prevention” as used herein means tostop a disease state or condition from occurring in an individualcompletely or almost completely or at least to a (preferablysignificant) extent, especially when the individual is predisposed tosuch a risk of contracting a disease state or condition.

The dispenser for intranasal administration of the pharmaceuticalcomposition described hereinabove is preferably a nasal spray or a nosedrop applicator. Nasal sprays and nose drop applicators are known in theart and e.g. disclosed in U.S. Pat. Nos. 2,577,321, 6,000,580 or EP 0170 198 A2. As used herein, the term “nose drop applicator” refers toany dispenser suitable for, especially intended for, the administrationof nose drops.

The inhalation device for administration of the pharmaceuticalcomposition described hereinabove (preferably to the lower respiratorytract) is preferably a metered-dose inhaler, a dry-powder inhaler or anebuliser.

A metered-dose inhaler is a device that aerosolises a pre-defined doseof a pharmaceutical composition (i.e. produces a comparatively shortburst of aerosol with a defined dose), usually for self-administrationby the patient. A metered-dose inhaler is for instance disclosed in U.S.Pat. No. 6,260,549 B1.

Dry-powder inhalers are devices for inhalation of dry-powderformulations by the patient. Such devices are for instance disclosed inU.S. Pat. Nos. 4,995,385 and 4,069,819. Established dry-powder inhalersare for instance SPINHALER®, ROTAHALER®, FLOWCAPS®, INHALATOR®,DISKHALER® and AEROLIZER®.

Nebulisers are devices that produce aerosols for inhalation, typicallycontinuously as long as they are switched on or breath-actuated.Established nebuliser products are for instance Aeroneb® and Pari®.Document U.S. Pat. No. 9,364,618 B2, e.g., also discloses a nebuliser.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention is further illustrated by the following figuresand examples, without being restricted thereto.

FIG. 1: 2-deoxyglucose inhibits HRV replication and HRV proteinexpression in vitro. Panel A) shows the impact of 2-DG on HRV 14replication in HeLa Ohio cells and primary human fibroblasts. Cells wereinfected for 1 h and washed in PBS before application of the agent inthe indicated concentration and incubation in full growth medium foradditional 6 h. After the incubation period, RNA was obtained andreversely transcribed to cDNA before assessing viral RNA load by qPCR. Asummary of 6 independent experiments is shown. *p<0.05 calculated byWilcoxon signed rank test of the normalized data. Panel B) shows theexpression of viral proteins VP1-3 in HRV 14 infected HeLa Ohio cells.Cells were infected as above ±2-DG treatment prior to lysis and westernblot analysis. A representative experiment of 2 independent experimentsperformed in duplicates is shown.

FIG. 2: 2-deoxyglucose is not toxic to human cells. Treatment with 10 mM2-deoxyglucose (in the presence or absence of HRV) has no significantinfluence on cell viability of HeLa cells. Cells were infected andtreated as above before application of a fluorescently labeled viabilitydye and flow cytometric assessment.

FIG. 3: 2-deoxyglucose reduces viral load and ameliorates inflammationcaused by HRV airway infection in vivo. C57BL/6 mice were infected withHRV 1B intranasally ±50 μL 5 mM 2-DG/50 μL PBS. After 24 h of infection,mice were euthanized, a bronchioalveolar lavage (BAL) performed andtissue obtained for qPCR and histological analysis. Shown is thepresence of HRV1B RNA in lung tissue normalized to hypoxanthineribosyltransferase (HPRT) expression, indicative of viral load, and thecount of leukocyte populations in the BAL (Total leukocytes=CD45+,Neutrophils=CD45+Ly6G+, B cells=CD45+CD19+, dendritic cells=CD45+CD11c+,T helper cells=CD45+CD3+CD4+, NK cells=CD45+NK1.1+), indicative of lunginflammation.

FIG. 4: 2-deoxyglucose ameliorates inflammation caused by HRV airwayinfection in vivo, as confirmed by histology. Depicted are tworepresentative haematoxylin and eosin (HE) stains of lung tissues ofHRV-challenged mice treated with placebo or 2-DG. A representativeexperiment of 2 independent experiments performed is shown. In eachexperiment, 10 mice per infection group were tested and 2 mice in theuninfected control-group. The placebo treated mouse has markedly moreperibronchiolar leukocyte infiltration than the 2-DG treated mouse.

EXAMPLE 1—CELL CULTURE AND IN-VITRO HRV INFECTION

Experiments involving human material were carried out according to theDeclaration of Helsinki principles after approval by the ethicscommittee of the Medical University of Vienna and after obtainingwritten informed consent from the participants (vote number 1149/2011:isolation and culture of cells from and analysis of normal human skinbiopsies).

HeLa cells (strain: Ohio, Flow laboratories) were cultivated in RPMI1640 supplemented with 2 mM 1-glutamine, (both Gibco Ltd., Paisley,Scotland), 100 U/mL penicillin, 100 μg/mL streptomycin (PAALaboratories, Austria) and 10% FCS (Gibco). For fibroblast isolation,tissue samples including skin and subcutaneous fat (100-300 cm²) wereobtained from patients undergoing routinely performed body contouringsurgeries and were used for the isolation of mast cells, fibroblasts,and keratinocytes. The skin was inconspicuous upon clinical inspectionand in histology. Subcutaneous tissue and reticular dermis were removedand the remaining split thickness skin was cut into 0.5 cm² pieces andplaced overnight at 4° C. in 2.4 U/ml dispase II (Roche, Vienna,Austria). After the separation of the epidermis, dermis was digested incollagenase I (Gibco, Vienna, Austria) at 37° C. for 2 h. CD117+ mastcells were isolated using magnetic beads (MACS System; Miltenyi Biotec,Bergisch Gladbach, Germany) according to the manufacturer'sinstructions. To increase the purity of recovered cells, magneticisolation was repeated with CD117+ cells from the first isolation round.CD117+ mast cells were then seeded in DMEM (Gibco) supplemented with 10%FCS, penicillin/streptomycin (both Biochrom, Berlin, Germany), and 100ng/ml recombinant human stem cell factor (PeproTech, Rocky Hill, N.Y.,USA). After the isolation of mast cells, CD117 adherent cells(=fibroblasts) were cultured in supplemented RPMI 1640 as above.(Gschwandtner et al., 2017)

HeLa Ohio cells or fibroblasts were plated on polystyrene platesovernight (Corning Incorporated, Corning, N.Y., USA). On the subsequentday, cells were infected with the indicated amount of 50% Tissue cultureInfective Dose (TCID 50) of HRV 14 (belonging to species Rhinovirus B)per cell (multiplicity of infection 3.5-10, depending on theexperiment). After 1 h of infection, cells were washed with 37° C.phosphate-buffered saline (PBS) and incubated another 6 h with medium±the indicated agent in the indicated concentration before furtherprocessing. For assessment of cell viability, cells were stained with afixable viability dye (65-0865-14; eBioscience, Vienna, Austria).

Western blot analysis: HeLa Ohio cells were infected as described above.After 7 h of infection, cells were lysed in 0.5% Triton-X buffer for 5min on ice. After lysis, the suspension was centrifuged for 5 min at13000×g, and the supernatant was utilized for further analysis. Westernblot analysis was performed as described before (Gualdoni et al., 2015).Anti-HRV VP1-3 antibody and anti-GAPDH were used in a dilution of1:1000. Detection was performed with Pierce® ECL Western blottingsubstrate (Thermo Fisher Scientific, Waltham, Mass.) on a LAS-4000(Fujifilm, Tokyo, Japan). Data analysis, quantification, and processingwere performed with Fiji (ImageJ) image processing software.

Results:

2-deoxyglucose strongly inhibited HRV reproduction both in HeLa cellsand in primary human fibroblasts (see FIG. 1A). To verify this impact onreproduction, the viral replication on protein level as mirrored by theexpression of viral protein (VP) 1-3 in HeLa cells was also analysed,which showed similar results as on RNA level (FIG. 1A). The agent2-deoxyglucose had no measurable impact on cell viability in theutilized doses (FIG. 2).

EXAMPLE 2—MURINE HRV INFECTION MODEL

All animal experimentation protocols were evaluated by the Animal EthicsCommittee of the Medical University of Vienna and approved by theMinistry of Economy and Science (BMWFW-66.009/0356_WF/V/3b/2015). Animalhusbandry and experimentation was performed according to the Federationof Laboratory Animal Science Association guidelines. Female C57BL/6 Jmice aged 6 to 8 wk from in-house breeding (originally obtained from TheJackson Laboratory, Bar Harbor, Me., USA) were used for all experiments.An animal care professional not related to the study performedallocation of mice to the groups randomly.

Experiments were performed according to a published protocol (Bartlettet al., 2008) with minor modifications. Mice were sedated withisoflurane and an inoculum of 5×10{circumflex over ( )}6 TCID50 of HRV1B(belonging to species Rhinovirus A) in PBS was applied intranasally.Either 5 mM 2-DG dissolved in PBS or PBS solo were simultaneouslyapplied intranasally. After 24 h, mice were euthanized and abronchioalveolar lavage performed. One lung lobe was obtained for PCRanalysis and one for histological examination. For PCR analysis,material was homogenized before RNA isolation with the RNEasy kit asabove. For histological analysis, lung lobes were fixed in 10%formaldehyde and embedded in paraffin. Lung sections (4 μm) were stainedwith H&E and evaluated by a pathologist blinded to group allocation.

Results:

In this well-established murine model of rhinovirus airway infection(Bartlett et al., 2008), 2-DG reduced HRV load in infected lung tissueand reduced virus induced lung inflammation (see FIGS. 3 and 4), in linewith the in vitro findings. There were no observable side effects on thetreated mice at all.

EXAMPLE 3—NASAL SPRAY

A nasal spray as e.g. disclosed in U.S. Pat. No. 6,000,580 is providedcontaining 10 ml of the following pharmaceutical composition: 10 mM2-deoxy-D-glucose, 0.9% w/v NaCl dissolved in sterile deionised water.

EXAMPLE 4— NOSE DROP APPLICATOR

A nose drop applicator as e.g. disclosed in EP 0 170 198 A2 is providedcontaining 5 ml of the following pharmaceutical composition: 0.5 mM2-deoxy-2-fluoro-D-mannose, 0.05% (w/v) oxymetazoline hydrochloride,0.05% (w/w) benzalkonium chloride, 85% (v/v) glycerol in steriledeionised water.

EXAMPLE 5— NEBULIZER

A nebuliser as e.g. disclosed in U.S. Pat. No. 9,364,618 B2 is providedcomprising the following pharmaceutical composition in its fluidreservoir: 35 mM 2-deoxy-D-glucose, 0.9% w/v NaCl dissolved in steriledeionised water. The nebuliser is used to deliver the composition byinhalation as an aerosol to the lower respiratory tract of animmune-suppressed patient suffering from a rhinovirus infection in thelungs.

NON-PATENT REFERENCES

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1. A method, comprising: obtaining a nasal spray containing apharmaceutically acceptable formulation comprising 2-deoxy-D-glucose;and spraying an amount of the formulation into one or both nostrils of ahuman individual, wherein the individual has a condition selected fromcommon cold, asthma and chronic obstructive pulmonary disease (COPD), orwherein the individual is at risk of developing a common cold.
 2. Themethod of claim 1, wherein the individual has the condition.
 3. Themethod of claim 2, wherein the condition is a common cold.
 4. The methodof claim 1, wherein the formulation is a liquid aqueous solution.
 5. Themethod of claim 1, wherein the concentration of 2-deoxy-D-glucose in theformulation is 0.1 mM-500 mM.
 6. The method of claim 5, wherein theconcentration of 2-deoxy-D-glucose in the formulation is 0.25 mM-250 mM.7. The method of claim 1, wherein the formulation comprises at least oneadditional active agent.
 8. The method of claim 7, wherein the at leastone additional active agent is decongestants or non-steroidalanti-inflammatory drugs (NSAIDs).
 9. The method of claim 8, wherein theat least one additional active agent is a decongestant comprisingnorepinephrine releasing agents, α-adrenergic receptor agonists, orcorticosteroids.
 10. The method of claim 9, wherein the at least oneadditional active agent is a decongestant comprising pseudoephedrine,ephedrine, phenylpropanolamine, oxymetazoline, xylometazoline,budesonide, flunisolide, or fluticasone.
 11. The method of claim 1,wherein the formulation comprises 2-deoxy-D-glucose as the single activeagent.
 12. The method of claim 2, wherein the formulation comprises2-deoxy-D-glucose as the single active agent.
 13. The method of claim 3,wherein the formulation comprises 2-deoxy-D-glucose as the single activeagent.
 14. The method of claim 1, wherein the 2-deoxy-D-glucose isadministered at a dose of 0.01 μmol-50 μmol.
 15. The method of claim 1,wherein the formulation is administered every other day for 2-14 days.16. The method of claim 1, wherein the formulation is administered dailyfor 2-14 days.
 17. The method of claim 1, wherein the formulation issprayed into both nostrils of the individual, and wherein theformulation is sprayed into each nostril independently.
 18. A method,comprising: obtaining a nasal spray containing a pharmaceuticallyacceptable formulation comprising 2-deoxy-D-glucose as the single activeagent, wherein the concentration of 2-deoxy-D-glucose in the formulationis 0.25 mM-500 mM, and wherein the formulation is a liquid aqueoussolution; and spraying an amount of the formulation into both nostrilsof a human individual, wherein the formulation is sprayed into eachnostril of the individual independently, and wherein the individual hasa common cold.
 19. A method, comprising: obtaining a nasal spraycontaining a pharmaceutically acceptable formulation comprising2-deoxy-D-glucose, wherein the concentration of 2-deoxy-D-glucose in theformulation is 0.25 mM-500 mM, wherein the formulation further comprisesa decongestant comprising norepinephrine releasing agents, α-adrenergicreceptor agonists, or corticosteroids, and wherein the formulation is aliquid aqueous solution; and spraying an amount of the formulation intoboth nostrils of a human individual, wherein the formulation is sprayedinto each nostril of the individual independently, and wherein theindividual has a common cold.
 20. The method of claim 19, wherein thedecongestant is pseudoephedrine, ephedrine, phenylpropanolamine,oxymetazoline, xylometazoline, budesonide, flunisolide, or fluticasone.